D(-)-.beta.-hydroxyisobutyric acid is used in the preparation of captopril, an angiotensin-converting enzyme inhibitor useful in the treatment of hypertension.
Until now, the preparation of D(-)-.beta.-hydroxyisobutyric acid has been accomplished by chemical synthesis and through the use of fermentation techniques.
With respect to chemical synthesis, .beta.-hydroxyisobutyric acid has been prepared from formaldehyde and ethyl [-bromopropionate by the Reformatsky reaction (E. E. Blaise et al., Ann. Chim. et Phys. 17,371, 1969) whereby the optically inactive DL(.+-.) form is obtained. Chemical resolution is employed to obtain the optically active D-(-) form (J. Retey et al., Biochemische Zeitschrift, 342, 256-271, 1965. In Journal of Biological Chemistry, 241, 868, 1966, M. Specter et al. disclose a method for obtaining the optically active D(-) form directly without need for optical resolution employing threo-3-methyl-L-aspartic acid as the starting material. Unfortunately, however, the procedure is complicated and expensive to carry out.
U.S. Pat. No., 4,310,635 to Hasegawa et al. discloses a fermentation method wherein isobutyric acid or methacrylic acid is converted into D(-)-.beta.-hydroxyisobutyric acid employing microorganisms, including those of the Candida genus such as Candida rugosa IFO 0750 and Candida rugosa IFO 0591, and appropriate culture broths. The product is isolated from the culture broth by solvent extraction and ion exchange, wherein the culture broth or reaction medium is acidified with a mineral acid such as sulfuric acid or hydrochloric acid, an inorganic salt is added, if necessary, to increase the ionic strength of the broth or mixture and a water-immiscible solvent such as butanol, methyl-isobutyl ketone or ethyl acetate is used to extract the product.
Japanese patent No. 178726 dated June 11, 1981 and assigned to Kanegafuchi Chem KK discloses a method for preparing D(-)-.beta.-hydroxyisobutyric acid by reacting isobutyl aldehyde, isobutylamine, or isobutyl alcohol with Candida, (such as Candida rugosa), Pichia, Torulopsis, Aspergillus, Choanephora, Wingea or Zygorhynchus. The patentee indicates good yield is obtained at a lower cost than obtained through optical resolution of DL(.+-.)-.beta.-hydroxy- isobutyric acid or asymmetrical oxidation of 2-methyl-1,3-propanediol or the fermentation process using isobutyric acid or methacrylic acid.